Alzheimer's disease (AD) extracts a massive and rapidly rising health care burden. The hypothesis that the Amyloid beta (Ass) peptide plays an early causative role is supported by pathology, by human genetics and by biomarker studies. More specifically, Ass oligomers trigger a toxic cascade that impairs synaptic function and subsequently leads to progressive cognitive dysfunction. Therapeutic efforts to intervene in the Ass pathway have focused on the production or clearance of the peptide, and have been disappointing so far. Additional validated targets for AD are needed. Previously, we have studied the basis for Ass oligomer (Asso) toxicity for neurons. Using an unbiased genome- wide screening method we searched for Ass oligomer-specific binding sites expressed in brain, and identified PrPC. Amongst reported Asso binding sites, only PrPC was identified through an unbiased, genome-wide screen. This finding raises the possibility that PrP antagonists might be AD therapeutics. The contribution of Asso/PrPC complexes to various preclinical AD models has been examined using gene knockout and anti-PrP antibodies. Certain phenotypes have been observed to occur in the absence of PrPC. In other paradigms, PrPC is essential for Asso-induced cell death and impaired synaptic plasticity, as well as AD transgene-induced spatial memory deficits, synapse loss, serotonin axon degeneration and early death. Critically, human AD brain-derived extracts require PrPC to suppress synaptic plasticity. Encouragingly, the treatment of aged, memory-impaired APP/PS1 mice with anti-PrPC antibody reverses memory deficits. We seek to develop PrPC antagonists as a novel class for AD therapy. Using high throughput chemical compound screening we have identified several hit compounds, which protect cells from the detrimental effects of Asso. We seek to develop structural activity relationships and pharmacokinetic data for these hits. We will search a broader chemical space using an assay focused on the purified N-terminal domain of PrPC which binds human AD derived Asso species. For selected PrP antagonist compounds, we will test preclinical therapeutic efficacy in mice. These experiments have the potential to provide preclinical proof of concept that the interaction of Asso with PrPC is an attractive therapeutic target for AD. Positive outcomes will justify further lead compound optimization and toxicology studies in preparation for clinical development.